Epidemiological studies indicate 6that estrogen hormone replacement therapy in postmenopausal women reduces the risk of Alzheimer's Disease. One mechanisms by which estrogen may reduce risk of Alzheimer's Disease is inhibition of beta-amyloid plaque formation and ensuing cell death in hippocampus and cortex, which are among the most severely affected brain regions in Alzheimer's Disease. Using cDNA array assays to screen for estrogen-regulated genes in a mouse model of menopause, three genes were identified that are both regulated by estrogen in the hippocampus and frontal cortex and are known to be involved in amyloid precursor protein (APP) processing, plaque formation, and apoptosis. These genes encode transthyretin precursor (TTR), presenilin 1 (PS1), and presenilin 2 (PS2). Presenilins promote neural degeneration by cleaving APP into plaque-forming beta-amyloid peptide fragments (Abeta42) and inducing apoptosis. In contrast, TTR impedes plaque formation by sequestering Abeta42. The cDNA array data suggest two novel mechanisms for neural protection by estrogen: 1) inhibition of PS1 and PS2 gene expression, and 2) stimulation of TTR gene expression. The goal of the proposed project is to confirm and extend the findings based on cDNA arrays. The Specific Aims are to 1) confirm and precisely quantify estrogen regulation of TTR, PS1, and PS2 mRNA and protein are regulated by estrogen using in situ hybridization histochemistry and immunocytochemistry. The proposed studies employed a newly developed in vivo mouse model of menopause in which tissue responses to estrogen are assessed and compared when hormone replacement therapy is begin in either early or late menopause. The long-term goal of this work is to contribute to the development of hormone replacement strategies for post-menopausal women that are optimally effective in delaying or preventing the progression of Alzheimer's Disease.